Abstract MP21: Associations Between Plasma Proteome, Leukocyte Telomere Length, and Polygenic Risk Score for Leukocyte Telomere Length: the Atherosclerosis Risk in Communities Study (ARIC)

Introduction: Leukocyte telomere length (LTL) is an important aging biomarker implicated in the pathogenesis of age-related conditions. We conducted a large-scale proteomics study to characterize the proteomic signatures of LTL and its genetic determinants measured by polygenic risk score (PRS). Hypothesis: We hypothesize that LTL and LTL PRS are associated with blood proteomic signatures linked to aging-related conditions. Methods: We used TelSeq to estimate LTL based on whole genome sequencing (WGS) data measured in samples collected in ARIC visits 1, 2, and 3 (i.e., the baseline for this study). TelSeq counted reads containing at least 12 TTAGGG repeats. This count was then normalized to the number of reads with GC content between 48% and 52%. Only samples with read lengths of 150 or 151 were included in subsequent analyses, and LTL estimates were inverse normalized within read length group and WGS group before being merged. We derived a PRS for LTL based on previously published genome-wide association study (GWAS) summary statistics for 150 significant autosomal SNPs and ARIC GWAS data. We then analyzed LTL or LTL PRS as a predictor and plasma levels of proteins as outcomes, measured at ARIC visit 2 (for the LTL PRS analysis) and visit 3 (for the LTL analysis) using SOMAscan v4 (~5,000 proteins). Race-specific linear regressions were performed to evaluate the association between LTL or LTL PRS and levels of each protein adjusting for potential confounders at baseline. We used a Bonferroni correction to account for multiple testing. The analysis in Whites served as a discovery (p≤1x10 -5 ) and that in Blacks as a replication. Results: The final sample sizes were as follows: LTL PRS analysis (n=7,587 Whites and 2,094 Blacks) and LTL analysis (n=5,014 Whites and 884 Blacks). In Whites, LTL PRS was significantly associated with five proteins (p≤1x10 -5 ) that also showed the same direction of association in Blacks: THPO, GP1Bα, PEAR1, KDR, and GP5, with the association for KDR reaching nominal significance in Blacks (p=0.02). For LTL as the predictor, GP1Bα, GDF15 and TXNDC5 were significant in Whites, with consistent direction of associations in Blacks (p>0.05). These proteins are linked to hemostasis (all), endothelial proliferation (KDR), heart disease and cancer (GDF15), and cancer and rheumatoid arthritis (TXNDC5) in the literature. Conclusion: This large-scale proteomic analysis reveals blood proteomic signatures for LTL PRS and LTL, which will likely improve the understanding of biological pathways and clinical conditions implicated by LTL.